Process for preparing tetrahydroquinoline derivatives

ABSTRACT

The invention relates to a novel process for preparing enantiomerically enriched or pure tetrahydroquinoline derivatives by reacting a chiral dihydropyran-methylamine C with a aldehyde B and an aniline A in a multicomponent one pot synthesis in the presence of a protonic acid or Lewis acid with a suitable solvent. A, B, C have the meaning as described in the specification.

The invention relates to a process for the manufacture ofenantiomerically enriched or pure compounds of formula I:

R^(a) denotes Hal, cyano, COOH, COOA, A, CF₃;

R¹ denotes H, A, Aryl, Het, Hal, —(CY₂)_(n)—SA, —(CY₂)_(n)—SCF₃,—(CY₂)_(n—SCN, —(CY) ₂)_(n)—CF₃, —(CY₂)_(n)—OCF₃, R, cycloalkyl, —SCH₃,—SCN, —CF₃, —OCF₃, —OA, ——(CY₂)_(n)—CO₂R, —(CY₂)_(n)—CN, —(CY₂)_(n)-Hal,—(CY₂)_(n)—NR₂, (CY₂)_(n)—OA, (CY₂)_(n)—OCOA, —SCF₃, (CY₂)_(n)—CONR₂,—(CY₂)_(n)—NHCOA, —(CY₂)_(n)—NHSO₂A, SF₅, Si(CH₃)₃, CO—(CY₂)_(n)—CH₃,—(CY₂)_(n)—N— Pyrolidon, (CH₂)_(n)NRCOOR, NRCOOR, NCO, (CH₂)_(n)COOR,NCOOR, (CH₂)_(n)OH, NR(CH₂)_(n)NR₂, C(OH)R₂, NR(CH₂)_(n)OR, NCOR,(CH₂)_(n)Ar, (CH₂)_(n)Het, (CH₂)_(n)R¹, (CH₂)_(n)X(CH₂)_(n)Ar,(CH₂)_(n)X(CH₂)_(n)Het, (CH₂)_(n)CONR₂, XCONR(CH₂)_(n)NR₂,N[(CH₂)_(n)XCOOR]CO(CH₂)_(n)Ar, N[(CH₂)_(n)XR]CO(CH₂)_(n)Ar,N[(CH₂)_(n)XR]CO(CH₂)_(n)XAryl, N[(CH₂)_(n)XR]SO₂(CH₂)_(n)Ar,N[(CH₂)_(n)NRCOOR]CO(CH₂)_(n)Ar, N[(CH₂)_(n)NR₂]CO(CH₂)_(n)Ar,N[(CH₂)_(n)NR₂]CO(CH₂)_(n)NRAr, N[(CH₂)_(n)NR₂]SO₂(CH₂)_(n)Ar,N[(CH₂)_(n)XR]CO(CH₂)_(n)Het, N[(CH₂)_(n)XR]CO(CH₂)_(n)XHet,N[(CH₂)_(n)XR]SO₂(CH₂)_(n)Het, N[(CH₂)_(n)NRCOOR]CO(CH₂)_(n)Het,N[(CH₂)_(n)NR₂]CO(CH₂)_(n)Het, N[(CH₂)_(n)NR₂]CO(CH₂)_(n)NRHet;

R², R³ denotes H, A, Hal, OA, OR;

denotes H, A, Hal, OR;

A denotes Alkyl or Cycloalkyl, wherein one or more H-atoms can bereplaced by Hal;

Hal denotes F, CI, Br or I;

R denotes H or A, in the case of geminal groups R together also—(CH₂)₅—, —(CH₂)₄— or —(CH₂)_(n)—X—(CH₂)_(n), or —(CH₂)_(n)—Z—(CH₂)_(n);

X denotes O, S or NR¹;

Q denotes CH₂—NH-A, CH₂—NH—C(O)R¹, CH₂—NH—SO₂R¹;

Z denotes CH₂, X, CHCONH₂, CH(CH₂)_(n)NR¹COOR¹, CHNR¹COOR¹, NCHO,CHCON(R¹)₂, CH(CH₂)_(n)COOR¹, NCOOR¹, CH(CH₂)_(n)OH, N(CH₂)_(n)OH,CHNH₂, CH(CH₂)_(n)NR¹ ₂, CH(CH₂)_(n)NR¹ ₂, C(OH)R¹, CHNCOR¹, NCOR¹,N(CH₂)_(n)Ar, N(CH₂)_(n)Het, CHR¹, NR¹, CH(CH₂)_(n)Ar, CH(CH₂)_(n)Het,CH(CH₂)_(n)R¹, N(CH₂)_(n)COOR¹, CH(CH₂)_(n)X(CH₂)_(n)Ar,CH(CH₂)_(n)X(CH₂)_(n)Het, N(CH₂)_(n)CON(R¹)₂, NSO₂R¹, CHSO₂N(R¹)₂,XCONR(CH₂)_(n)N(R¹)₂, NCO(CH₂)_(n)Ar, NCO(CH₂)_(n)XAr, NSO₂(CH₂)_(n)Ar,NCO(CH₂)_(n)Ar, NCO(CH₂)_(n)NR¹Aryl, NCO(CH₂)_(n)Het, NCO(CH₂)_(n)XHet,NSO₂(CH₂)_(n)Het, NCO(CH₂)_(n)NR¹Het, N(CH₂)_(n)NR₂CH,CHO(CH₂)_(n)N(R¹)₂, CHX(CH₂)_(n)N(R¹)₂, NCO(CH₂)_(n)NR₂,

R⁶ denotes unsubstituted Ar or Het which is substituted in at least oneposition by Hal, NO₂, CN, OR, A, —(CY₂)_(n)—OR, —OCOR, —(CY₂)_(n)—CO₂R,—(CY₂)₂)_(n)—CN, —NCOR, —COR or —(CY₂)_(n)—NR₂ or by Aryl or Het whichalso may be substituted by Hal, NO₂, CN, A, OR, OCOR, COR, NR₂, CF₃,OCF₃, OCH(CF₃)₂,

R⁷ denotes (C═O)—R, (C═O)—NR₂, (C═O)—OR, H or A;

Ar denotes a monocyclic or bicyclic, saturated, unsaturated or aromaticcarbocyclic ring having 6 to 14 carbon atoms which may be unsubstitutedwhich is substituted in at least one position by Hal, NO₂, CN, OR, A,—(CY₂)_(n)—OR, —OCOR, —(CY₂)_(n)—CO₂R, —(CY₂)_(n)—CN, —NCOR, —COR or—(CY₂)_(n)—NR₂ or by Hal, NO₂, CN, A, OR, OCOR, COR, NR₂, CF₃, OCF₃,OCH(CF₃)₂;

Het denotes a monocyclic or bicyclic, saturated, unsaturated or aromaticheterocyclic ring having 1 to 4 N, O and/or S atoms which may beunsubstituted or which is substituted in at least one position by Hal,NO₂, CN, OR, A, —(CY₂)_(n)—OR, —OCOR, —(CY₂)_(n)—CO₂R, —(CY₂)_(n)—CN,—NCOR, —COR or —(CY₂)_(n)—NR₂ or by Hal, NO₂, CN, A, OR, OCOR, COR, NR₂,CF₃, OCF₃, OCH(CF₃)₂;

n denotes 0, 1, 2 3, 4, 5, 6 or 7;

as well as their pharmaceutically acceptable derivatives, solvates,tautomers, salts and polymorphic forms.

Processes according to the invention are relating to the manufacture ofenantiomerically enriched or pure compounds of formula Ia

wherein R¹ to R⁷ has the meaning given above and R^(a) is Hal, cyano,COOH, COOA or A.

Most preferred processes according to the invention are relating to themanufacture of enantiomerically enriched or pure compounds of formulaIa1

wherein R¹ to R⁷, Ar has the meaning given above and R^(a) is Hal,cyano, COOH, COOA or A.

Very most preferred processes according to the invention are relating tothe manufacture of enantiomerically enriched or pure compounds formulaIa₂:

(1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea)is obtained by the inventive process.

Processes according to the invention are relating to the manufacture ofenantiomerically enriched or pure enantiomers of formula Ib

wherein R¹ to R⁷ has the meaning given above and R^(a) is Hal, cyano,COOH, COOA or A.

Most preferred processes according to the invention are relating to themanufacture of enantiomerically enriched or pure compounds of formulaIb₁

wherein R¹ to R⁷, Ar has the meaning given above and R^(a) is Hal,cyano, COOH, COOA or A.

Very most preferred Processes according to the invention are relating tothe manufacture of enantiomerically enriched or pure compounds offormula I₂:

((2R,4aS,5R,10bS)-9-Chloro-7-fluoro-5-phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-methyl-amine.

The invention relates also to compound of formula C and theirenantiomerically enriched or pure enantiomers:

wherein C is as described above as well as their pharmaceuticallyacceptable derivatives, solvates, tautomers, salts and polymorphicforms.

The invention relates also to compound of formula C′ and theirenantiomerically enriched or pure enantiomers:

wherein R¹ is as described above as well as their pharmaceuticallyacceptable derivatives, solvates, tautomers, salts and polymorphicforms.

The invention relates also to a process for the manufacture of pureenantiomers compounds of formula C:

wherein Q denotes CH₂—NH-A, CH₂—NH—C(O)R¹, CH₂—NH—SO₂R¹ and R¹ is asdescribed above as well as their pharmaceutically acceptablederivatives, solvates, tautomers, salts and polymorphic forms.

The invention relates also to a process for the manufacture of pureenantiomers compounds of formula C′:

wherein R¹ is as described above as well as their pharmaceuticallyacceptable derivatives, solvates, tautomers, salts and polymorphicforms.

The term enantiomerically enriched or pure preferably refers to anenantiomeric purity of above 60%, such as about 80% to about 100%.Especially the term refers to an enantiomeric purity of higher thanabout 98%.

The compound of formula I as well as therapeutically acceptable saltsthereof, are described in WO 2005/063735.

The compound of formula I is therapeutically active and especiallyuseful in the treatment of proliferative diseases.

The phenyl-hexahydro-2H-pyranoquinolin core of the compounds of formulaI can be obtained by aza-Diels-Alder reaction (see Magesh et al.Bioorganic & Medicinal Chemistry Letters 14 (2004) 2035-2040, Yadav eta. Tetrahedron 59 (2003), 1599-1604) or by reaction of a dihydropyranmoiety with a benzaldehyde moiety in a presence of an aniline derivativeand SOCl₂ (see Biswanath et al. Journal of Chemical Research, (12),793-795 (2005). The synthesis can be also carried out by reacting ananiline derivative with a benzaldehyde group in the presence of vinylderivatives as described in WO2005063735. This synthesis relates tocompounds, wherein the dihydropyran moiety used is not substituted andalso not chiral. It has been shown that hexahydro-2H-pyranoquinolinderivatives (family of tetrahydroquinolines, THQ's) and, especiallyPhenyl-hexahydro-2H-pyranoquinolin-2-methylamines are potent inhibitorsof kinesin Eg5 (WO2005063735). It has also be shown that an enantiopureor enantiomerically enriched form of the drug shows improved activityagainst the biological target. Compounds containing a THQ core displayproven strong mutagenic, carcinogenic and conjecturally teratogeniceffects on living organisms and mammals. Moreover, as the compounds areEg5 kinesin inhibitors they interact directly with the cell divisioncycle of living organisms. Consequently, THQ amines have to beclassified as highly potent and cytotoxic compounds and during the THQamine production, shipping and handling special and expensive safetymeasures have to be installed. A new synthesis route towards enantiopureTHQ amines, in which the THQ core is installed in one of the latersynthesis steps, preferably the last synthesis step, would help todecrease these special safety measures significantly. The presentinvention provides a new synthetic route that provides enantiomericallyenriched or pure forms of compounds of formula I from a respectiveenantiomerically enriched or pure chiral dihydropyran methyl aminederivative in a one pot synthesis in the presence of aniline andbenzaldehyde derivative. The present invention also provides anadvantageous synthetic route that will minimize safety measures andcosts considerably. The invention provides also new pure stereoisomersof dihydropyran methylamine derivatives.

The compounds of the present invention are used for the treatment andprophylaxis of diseases that are influenced by inhibition, regulationand/or modulation of the mitotic motor proteins, especially the mitoticmotor protein Eg5. These are predominantely all types of cancer andother neoplastic diseases.

The compounds of the formula I and salts thereof are obtained by thefollowing process, characterised in that a compound of formula A

in which R¹, R² and R³ have the meanings indicated above,

is reacted with a compound of the formula B

in which

R⁶ has the meaning indicated above,

and with a compound of the formula C,

wherein Q is described above,

More preferably the compounds of the formula I and salts thereof areobtained by the following process, characterised in that a compound offormula A

in which R¹, R² and R³ have the meanings indicated above,

is reacted with a compound of the formula B

in which R⁶ has the meaning indicated above,

and with a dihydropyran methylamine derivative of the formula C′,

wherein R¹ is as defined above. Preferably the reactions are carried outin the presence of a suitable solvent, preferably acetonitrile and aprotonic acid or Lewis acid, such as, for example, trifluoroacetic acid,hexafluoroisopropanol, bismuth(III) chloride, ytterbium(III) triflate,scandium(III) triflate or cerium(IV) ammonium nitrate, preferablytrifluoroacetic acid. The amino derivatives and preferably the compoundsof formula I, wherein Q is CH₂NH₂, are may be further transformed intothe other compounds of formula I by known procedures, such asalkylation, or acylation.

More surprisingly, it has been found that any acid addition salt of theamino-didropyrane C′ or the compound of formula C can be directlyapplied to the synthesis of the compounds of formula I instead of thefree base first, in order to obtain compounds according to formula I.This advantage avoid tedious filtration steps.

Preferred chiral salt of compound related to formula C and C′ areL-tosylproline or benzoyl tartraic acid salts and especially(2R,3R)-(−)-Di-O-benzoyl tartaric acid salts, more preferably the saltis L-tosylprolinate.

Above and below, the radicals R^(a), R¹, R², R³, R⁶, R⁷, X, Y, Q, Z, andn have the meanings indicated for the formula I, unless expresslyindicated otherwise. If individual radicals occur a number of timeswithin a compound, the radicals adopt the meanings indicated,independently of one another.

A denotes alkyl, is preferably unbranched (linear) or branched, and has1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A preferably denotes methyl,furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl ortert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1- ,1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, furthermore preferably, for example,trifluoromethyl.

A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 Catoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethylor 1,1,1-trifluoroethyl. A also denotes cycloalkyl.

Cycloalkyl preferably denotes cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl, but in particular cyclopentyl.

R^(a) preferably denotes A, Hal. In particular R^(a) preferably denotestert-butyl, isopropyl, CF₃, Cl or Br.

R¹ preferably denotes A, CF₃, OCF₃, SA, SCN, CH₂CN, —OCOA, Hal, SCF₃,preferably also t-butyl, —CH(CH₃)CH₂CH₃, isopropyl, ethyl or methyl. Inparticular, R¹ denotes t-butyl, isopropyl, ethyl, CF₃, methyl, Br, Cl,SCF₃, CH(CH₃)CH₂CH₃, n-propyl, OCH₃, SCH₃, n-butyl, —SCN, CH₂CN. R¹particularly preferably denotes t-butyl, isopropyl, ethyl or CF₃.

R² preferably denotes H, Hal, A or OA, in particular Br, cyclopropyl,OCH₃. Particular preference is furthermore given to H or F.

R³ preferably denotes H or A, in particular H. R³ is preferably in the5-position. In particular, R³ denotes H or F.

If the radicals and indices, such as, for example, n, occur more thanonce, the radicals and indices may, independently of one another, adoptdifferent values.

R⁶ preferably denotes phenyl, 2-, 3- or 4-pyridyl, pyrimidyl, furyl orthienyl, each of which is unsubstituted or mono- or polysubstituted byHal, CN, NO₂, OH, CF₃, OCH(CF₃)₂, OCOCH₃ or A. R⁶ is preferably not aheteroaromatic radical. In particular, R⁶ denotes unsubstituted phenylor one of the following groups:

in which

X denotes O, S or NR and in particular O or S, A has the meaningindicated above, but preferably denotes methyl, and Hal preferablydenotes F or Cl.

Particular preference is furthermore given to compounds of the formula Iin which R⁶ has one of the following meanings:

R⁷ preferably denotes H or A, in particular H.

Aryl preferably denotes phenyl, naphthyl or biphenyl, each of which isunsubstituted or mono-, di- or trisubstituted by Hal, A, OH, OA, NH₂,NO₂, CN, COOH, COOA, CONH₂, NHCOA, NHCONH₂, NHSO₂A, CHO, COA, SO₂NH₂,SO₂A, —CH₂—COOH or —OCH₂—COOH.

Aryl preferably denotes phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- orp-methoxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-,m- or p-(N-methylamino)phenyl, o-, m- orp-(N-methylaminocarbonyl)phenyl, o-, m- or p-acetamidophenyl, o-, m- orp-methoxyphenyl, m- or p-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl,o-, m- or p-(N,N-dimethylamino)phenyl, o-, m- orp-(N,N-dimethyl-aminocarbonyl)phenyl, o-, m- or p-(N-ethylamino)phenyl,o-, m- or p-(N,N-diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m- or p- chiorophenyl, o-, m- orp-(methylsulfonamido)phenyl, o-, m- or p-(methylsulfonyl)phenyl,furthermore preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl,2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl,3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-,2-amino-5-chloro- or 2-amino-6-chlorophenyl,2-nitro-4-N,N-dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl,2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Heteroaryl preferably denotes a mono- or bicyclic aromatic heterocyclehaving one or more N, O and/or S atoms which is unsubstituted or mono-,di- or trisubstituted by Hal, A, NO₂, NHA, NA₂, OA, COOA or CN.

Heteroaryl particularly preferably denotes a monocyclic saturated oraromatic heterocycle having one N, S or O atom, which may beunsubstituted or mono-, di- or trisubstituted by Hal, A, NHA, NA₂, NO₂,COOA or benzyl.

Irrespective of further substitutions, unsubstituted heteroaryl denotes,for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-,2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl,3-, 4- or 5-isoxazolyl 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl,2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or5-benzimidazolyl,. 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-,6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-,4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-,4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-,7- or 8-2H-benzo-1,4-oxazinyl, furthermore preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl or2,1,3-benzoxadiazol-5-yl.

Hal preferably denotes F, Cl or Br, but also I, particularly preferablyF or Cl.

Throughout the invention, all radicals which occur more than once may beidentical or different, i.e. are independent of one another.

The compounds of the formula I and also the starting materials for theirpreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry] 1992, Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use may also be made here of variants known per se which are notmentioned here in greater detail.

If desired, the starting materials may also be formed in situ so thatthey are not isolated from the reaction mixture, but instead areimmediately converted further into the compounds of the formula I.

The reaction is generally carried out in an inert solvent, preferably inthe presence of a protonic acid or Lewis acid, such as TFA, HFIP,bismuth(III) salts, ytterbium(III) salts or CAN. Depending on theconditions used, the reaction time is between a few minutes and 14 days,the reaction temperature is between about 0° and 180° , normally between0° and 100° , particularly preferably between 15° and 35° C.

Suitable inert solvents are, for example; hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; nitriles, such as acetonitrile; carbondisulfide; carboxylic acids, such as formic acid or acetic acid; nitrocompounds, such as nitromethane or nitrobenzene, or mixtures of the saidsolvents.

Compounds of the formula I in which R⁷ has a meaning other than H arepreferably prepared by alkylation or acylation from the compounds of theformula I in which R⁷ denotes H.

If desired, a functionally modified amino and/or hydroxyl group in acompound of the formula I can be liberated by solvolysis orhydrogenolysis by conventional methods. This can be carried out, forexample, using NaOH or KOH in water, water/THF or water/dioxane attemperatures between 0 and 100° .

The reduction of an ester to the aldehyde or alcohol or the reduction ofa nitrile to the aldehyde or amine is carried out by methods as areknown to the person skilled in the art and are described in standardworks of organic chemistry.

The examples and processes as described which follow will furtherillustrate the preparation of the compounds of the invention but are notintended to limit the scope of the invention as defined hereinabove oras claimed below.

In a preferred embodiment, he invention relates to compound of formula Cand their enantiomerically enriched or pure enantiomers:

wherein Q is as described above as well as their pharmaceuticallyacceptable derivatives, solvates, tautomers, salts and polymorphicforms.

In a very most preferred embodiment the invention relates to compoundsaccording to formula C wherein Q is , —CH₂—NHA, —CH₂—NHR¹, morepreferably —CH₂-Me or —CH₂—NH—CONH—CH₂—CH₂—N(Me)₂.

In a preferred embodiment the invention relates also to compound offormula C′ and their enantiomerically enriched or pure enantiomers:

wherein R¹ is as described above as well as their pharmaceuticallyacceptable derivatives, solvates, tautomers, salts and polymorphicforms.

In a very most preferred embodiment the invention relates to compoundsaccording to formula C′ wherein R¹ is Me or —CONH—CH₂—CH₂—N(Me)₂.

In a preferred embodiment, the invention relates to a process for themanufacture of enantiomerically enriched or pure compounds of formula C:

wherein Q is CH₂—NH_(A), more preferably CH₂—NH₂ as well as itspharmaceutically acceptable derivatives, solvates, tautomers, salts andpolymorphic forms comprising the following steps:

-   -   a) reacting 3,4-dihydro-2H-pyran-2-carbaldehyde with ammonia or        a primary alkylamine, such as methylamine in presence of a        catalyst and hydrogen to give the corresponding racemic amine,        and preferably dihydropyran methylamine salts;

Dihydropyranmethylamine

-   -   b) treating the racemic amine with a chiral acid compound in a        polar solvent to give the pure enantiomeric amine salts, and        preferably dihydropyran methylamine salts;    -   c) optionally treating the amine, and preferably the        dihydropyran(DHP) methylamine with a base to obtain compound C        in form of a free base.

In a preferred embodiment, the invention relates to a process for thesynthesis of compounds according to formula I which starts withcommercially available DHP-aldehyde (DHPA) which is allowed to reactwith ammonia or various primary amines, such as alkylamines, preferablymethyl amine. Under Raney-Co catalysis in a suitable solvent such as THFin presence of hydrogen a racemic DHP-alkylamine and preferablyDHP-methylamine is formed (See patent DE1233411), as show below.

wherein R¹ is as described above, more preferably R¹ is H, CH₃, alkyl,Aryl or Heteroaryl.

In a preferred embodiment the racemic DHP-methylamine is allowed tocristallize with a variety of chiral acids in different solvents to giveenantiomerically enriched DHP-alkylamine and preferably DHP-methylamineof formula C′.

Chiral acids used in this step are preferably tartaric chiral acids orproline, most preferably tartaric chiral acid is(2R,3R)-(−)-di-O-benzoyl tartaric acid, and proline is L-tosylproline.

In a preferred embodiment resolution of primary amine according toformula C and/or C′ will take place with chiral proline derivatives,especially with L-tosylproline.

In a preferred embodiment resolution of secondary amine according toformula C and/or C′ will take place with tartaric chiral acid,especially with (2R,3R)-(−)-di-O-benzoyl tartaric acid.

Surprisingly, it was found that for subsequent reactions compounds offormula C′ can be used in form of L-tosyl proline salt or as free base.In order to obtain the free base of compounds of formula C′, the chiralenantiomerically enriched or pure salt, preferably the L-tosyl prolinesalt of the amine needs to be treated with a strong base such as NaOHpreferably 2N NaOH.

Experimental:

It is found for mixtures of compounds of formula C′ wherein R¹ ismethyl, and its antipode that the treatment with equimolar amounts ofL-tosylproline in ethanol preferably leads to crystals with the(R)-configured DHP-methylamine The enantiomeric purity was determined bychiral HPLC to be er=93:7 for the desired (R)-DHP-methylamineenantiomer. Recrystallization from ethanol provided the(R)-DHP-methylamine (as L-tosyl proline salt) in er>99:1 enantiomericpurity (determined by chiral HPLC). For the subsequent reactions(R)-DNP-methylamine can be used as L-tosyl proline salt or as free base.In order to obtain the free base of (R)-DHP-methylamine, the L-tosylproline salt is removed by treatment with a strong base, such as NaOH,preferably 2 N NaOH, according to the following scheme:

It is found for mixtures of compounds of formula C′ wherein R¹ when R¹is H and its antipode that the treatment with (2R,3R)-(−)-di-O-benzoyltartaric acid in 2-propanol leads to crystals with the (R)-configuredDHP-methylamine. The enantiomeric purity was determined by chiral HPLCto be er=84:16 for the desired (R)-DHP-methyl-N-methylamine enantiomer.Repeated recrystallization from 2-propanol provided the(R)-DHP-methyl-N-methylamine (as (2R,3R)-(−)-di-O-benzoyl tartaric acidin er>99:1 enantiomeric purity (determined by chiral HPLC). For the nextreactions amine can be used as (2R,3R)-(−)-di-O-benzoyl tartaric acidsalt or as free base. In order to get the free base the(2R,3R)-(−)-di-O-benzoyl tartaric acid salt of amine is removed bytreatment with a strong base, such as NaOH, preferably 2N NaOH,according to the following scheme:

In a preferred embodiment, enantiomerically pure DHP-methylamines can betransformed in different other compounds classes like substitutedDHP-methylamines DHP-methylamides, DHP-methylureas,DHP-methylsulfonamides or tertiary DHP-methylamines from DHP-methylaminechiral salts or the corresponding free base according to the followingscheme:

wherein R¹ is as defined above and LG is a leaving group such ashalogen, mesylate or tosylate, the base is a strong non nucleophilicbase such as DBU or alkali-carbonate like such as Na₂CO₃ or K₂CO₃ andthe solvent is a polar solvent such as DMF.

In a preferred embodiment, DNP-methylamides can be prepared by reactingacid R¹—COOH with DHP-methylamine chiral salts or the corresponding freebase with a coupling agent and the presence or absence of a suitablebase in a polar solvent according to the following scheme:

wherein R¹ is as defined above and the coupling agent is selected fromBOP reagent, CDI, DCC, DEPBT, DIC, EDC.HCl, HATU, HBTU, HOAt,HOBt(anhydrous), HOOBt, HCTU, Cl—HOBt, PyBOP, PyBrOP, TBTU, TDBTU, TSTUor 4,5-dicyanoimidazole, the base, if needed, is selected fromtriethylamine or other alkylamines and the polar solvent is selectedfrom DMF.

In a preferred embodiment, DHP-methylamides can be prepared by reactingacyl chloride R¹—COCl with DHP-methylamine chiral salts or thecorresponding free base with the presence or absence of a suitable basein a polar solvent according to the following scheme:

wherein R¹ is as defined above and the base, if needed, is selected fromtriethylamine and other alkylamines and the polar solvent is selectedfrom DMF.

In a preferred embodiment DHP-methylsulfonamides can be prepared byreacting sulfonyl chloride R¹—SO₂Cl with DHP-methylamine chiral salts orthe corresponding free base with the presence or absence of a suitablebase in a polar solvent according to the following scheme:

wherein R¹ is as defined above and the base, if needed, is selected fromtriethylamine and other alkylamines and the polar solvent is selectedfrom DMF.

In a preferred embodiment DHP-methylureas can be prepared by reactingthe coupling agent CDI with DHP-methylamine chiral salts or thecorresponding free base and primary amine NH₂—R¹ with the presence orabsence of a suitable base in a polar solvent.

In a preferred embodiment, the invention relates to a process for thesynthesis of compounds according to formula I wherein C derivatives suchas DHP-amides, DHP-ureas, DHP-sulfonamides, and tertiary DHP-aminesreact in a multicomponent reaction mediated by a protonic acid or lewisacid in a polar solvent with anilines of type A and aldehydes of type Bto form THQ derivatives.

wherein R^(a), R², R³, R⁶, Q are as defined above and the protonic acidis preferably TFA and the polar solvent is preferably MeCN.

In a more preferred embodiment, the invention relates to a process forthe synthesis of compounds according to formula I wherein C′ derivativessuch as DHP-metylamides, DHP-methylureas, DHP-methylsulfonamides, ortertiary DHP-methylamines react in a multicomponent reaction mediated bya protonic acid or lewis acid in a polar solvant with anilines of type Aand aldehydes of type B to form THQ derivatives.

wherein R^(a), R¹, R², R³, R⁶, are as defined above and the protonicacid is preferably TFA and the polar solvent is preferably MeCN.

In a more preferred embodiment the invention relates to a process forthe synthesis of compounds according to formula I wherein C′ derivativessuch as DHP-methylamides, DHP-methylureas, DHP-methylsulfonamides, andtertiary DHP-methylamines react in a multicomponent reaction mediated bya protonic acid or lewis acid in a polar solvant with anilines of type Aand Arylaldehydes of type B wherein R⁶ is aryl, to form THQ.

wherein R^(a), R¹, R², R³ are as defined above and the protonic acid ispreferably TFA and the polar solvent is preferably MeCN.

In a more preferred embodiment the invention relates to a process forthe synthesis of compounds according to formula I in a pure enantiomericform wherein the THQ obtained previously from C is crystallized withchiral salts to give the corresponding exo-enantiomer of THQ.

wherein R^(a), R¹, R², R³, R⁶ are as defined above and the protonic acidis preferably TFA and the polar solvent is preferably MeCN. For therecristallization step the chiral salts is selected from tartaric saltsespecially (2R,3R)-(−)-di-O-benzoyl tartaric acid and the polar solventis ethanol.

In a more preferred embodiment the invention relates to a process forthe synthesis of compounds according to formula I in a pure enantiomericform wherein the THQ obtained previously from C′ is crystallized withchiral salts to give the corresponding exo-enantiomer of THQ.

wherein R^(a), R¹, R², R³, R⁶ are as defined above and the protonic acidis TFA and the polar solvent is MeCN. For the recristallization step thechiral salts is selected from tartaric salts especially(2R,3R)-(−)-di-O-benzoyl tartaric acid and the polar solvent is ethanol.

In a more preferred embodiment the invention relates to a process forthe synthesis of compounds according to formula I in a pure enantiomericform wherein the THQ obtained previously from C is crystallized withchiral salts to give the corresponding exo-enantiomer of THQ.

wherein R^(a), R¹, R², R³, are as defined above and the protonic acid ispreferably TFA and the polar solvent is preferably MeCN. For therecristallization step the chiral salts is selected from tartaric saltsespecially (2R,3R)-(−)-di-O-benzoyl tartaric acid and the polar solventis preferably ethanol.

In a more preferred embodiment the invention relates to a process forthe synthesis of compounds according to formula I in a pure enantiomericform wherein the THQ obtained previously from C′ is crystallized withchiral salts to give the corresponding exo-enantiomer of THQ.

wherein R^(a), R¹, R², R³, are as defined above and preferably whereinR^(a) is Cl, R¹ is CH₃, R² is F and R³ is H, the protonic acid ispreferably TFA and the polar solvent is preferably MeCN. For therecristallization step the chiral salts is selected from tartaric saltsespecially (2R,3R)-(−)-di-O-benzoyl tartaric acid and the polar solventis preferably ethanol.

EXAMPLES A) Preparation of a RacemicC-(3,4-Dihydro-2H-pyran-2-yl)-methylamine

3,4-Dihydro-2H-pyran-2-carbaldehyde (950 g, 8.31 mol) was dissolved inprecooled tetrahydrofuran (1.9 kg). Raney-Co catalyst (95 g,tetrahydrofuran moist) was added. Liquid ammonia (1350 g, 79.4 mol) wastransferred into the solution within 15 minutes. Hydrogen (186.2 L) wasadjusted to pressure 105 bar and the solution was stirred for 2 h at100° C. The reaction vessel was cooled to room temperature, the gasremoved and the solution degassed. The solution was concentrated underreduced pressure. The crude product (932 g) was distilled at reducedpressure to receive C-(3,4-Dihydro-2H-pyran-2-yl)-methylamine (702 g,6.17 mmol, 74% yield). Analytical data : Bp. 77-82° C. (30-32 mbar);HPLC-MS: (M+H)+=114 at rt=0.665 min. (TIC), rt=0.644 min. (UV), rt=0.616min. (ELS), Chromolith SpeedROD RP-18e 50-4.6 mm, solvent A: water+0.1%TFA, solvent B: acetonitrile+0.1% TFA, gradient: 4% solvent B at 0.0min., 100% solvent B at 2.6 min., flow: 2.4 mL/min., UV: 220 nm.

B) Preparation of Racemic (3,4-Dihydro-2H-pyran-2-ylmethyl)-methyl-amine

3,4-Dihydro-2H-pyran-2-carbaldehyde (300 g, 2.68 mol) was dissolved intetrahydrofuran (710 mL). Raney-Co catalyst (30 g, tetrahydrofuranmoist) was added. Gaseous methyl amine (415.4 g, 13.4 mol) wastransferred into the solution within 50 minutes (45° C.). Hydrogen (49.2L) was added and the pressure adjusted to 100 bar and the solution wasstirred for about 2 h at 100° C. The reaction vessel was cooled to roomtemperature, the gas removed and the solution degassed. The solution wasconcentrated under reduced pressure. The crude product (344.5 g) wasdistilled at reduced pressure to receive(3,4-Dihydro-2H-pyran-2-ylmethyl)-methyl-amine (289.8 g, 2.28 mol, 85%yield). Analytical data amine(3,4-Dihydro-2H-pyran-2-ylmethyl)-methyl-amine: Bp. 55-57° C. at 16mbar; HPLC-MS: (M+H)⁺=128 at r_(t)=0.619 min. (TIC), r_(t)=0.596 min.(UV), r_(t)=0.631 min. (ELS), Chromolith SpeedROD RP-18e 50-4.6 mm,solvent A: water+0.1% TFA, solvent B: acetonitrile+0.1% TFA, gradient:4% solvent B at 0.0 min., 100% solvent B at 2.6 min., flow: 2.4 mL/min.,UV: 220 nm.

C) Preparation of Enantiomerically PureC-(3,4-Dihydro-2H-pyran-2-yl)-methylamine (L-tosylproline salt) andEnantiomerically Pure C-(3,4-Dihydro-2H-pyran-2-yl)-methylamine (FreeBase)

Under gentle heating L-tosyl proline (119 g, 442 mmol) was dissolved inethanol (1000 mL). The solution was filtrated and the filter rinsed outwith hot ethanol (200 mL). C-(3,4-Dihydro-2H-pyran-2-yl)-methylamine(100 g, 884 mmol) and ethanol (200 mL) was added and heated to reflux.The solution was allowed to cool down under gentle stirring (˜100U/min.). At ˜50° C. a small portion of seeding crystals ofC-(3,4-Dihydro-2H-pyran-2-yl)-methylamine (er=>99.5:0.5 by chiral HPLC,crystals derived from earlier experiments) were added. The solution wasallowed to cool down to room temperature. During this time (18 h) a saltcrystallized. The salt was filtered off and washed with a small amountof cold ethanol to yield amine saltC-(3,4-Dihydro-2H-pyran-2-yl)-methylamine (98.5 g, er=93.2:6.8 by chiralHPLC). In order to receive enantiopure crystalsC-(3,4-Dihydro-2H-pyran-2-yl)-methylamine salt (98.5 g, er=93.2:6.8 bychiral HPLC) was dissolved under gentle heating in ethanol (850 mL) andcrystallization was performed under the same conditions as describedabove to receive amine salt of C-(3,4-Dihydro-2H-pyran-2-yl)-methylamine(83.1 g, er=98.6:1.4 by chiral HPLC).C-(3,4-Dihydro-2H-pyran-2-yl)-methylamine salt (83.1 g, er=98.6:1.4 bychiral HPLC) was dissolved in ethanol (400 mL) and subjected to the samecrystallization procedure as described above to yieldC-(3,4-Dihydro-2H-pyran-2-yl)-methylamine salt (77.8 g, 46% of thetheoretical yield, er=99.5:0.5 by chiral HPLC) in clear, colourlesscrystals. Analytical data C-(3,4-Dihydro-2H-pyran-2-yl)-methylaminesalt: Mp. 177-178° C.; [α]_(D) ²⁰−134.0° (c=0.995, MeOH); chiral HPLC:r_(t)E1=10.56 min., r_(t)E2=16.24 min. (er_(E1/E2)=0.5/99.5), CrownpakCR(+), HClO₄ pH1+10% methanol, flow: 0.8 mL/min., UV: 215 nm.C-(3,4-Dihydro-2H-pyran-2-yl)-methylamine salt (45.8 g, 120 mmol) wasdissolved in water (100 mL) and 2 N aqueous NaOH (80 mL) was added. Thesolution was extracted five times with dichloromethane (100 mL). Theorganic layer was washed with water (50 mL) and dried with sodiumsulphate to yield after distillation under reduced pressureC-(3,4-Dihydro-2H-pyran-2-yl)-methylamine (free base) (13.3 g, 98%,er=99.4: 0.6 by chiral HPLC) as colourless liquid. Analytical dataC-(3,4-Dihydro-2H-pyran-2-yl)-methylamine: Bp. 77-82° C. (30-32 mbar);[α]_(D) ²⁰=−75.8° (c=0.528, MeOH); chiral HPLC: r_(t)E1=10.2 min.,r_(t)E2=14.7 min. (er_(E1/E2)=0.6/99.4), Crownpak CR(+), HClO₄ pH1 +10%methanol, flow: 0.8 mL/min., UV: 215 nm.

D) Preparation of Enantiomerically Pure(3,4-Dihydro-2H-pyran-2-ylmethyl)-methyl-amine[(2R,3R)-(−)-Di-O-benzoylTartaric Acid Salt] and Free Base

Under gentle heating (2R,3R)-(−)-di-O-benzoyl tartaric acid (47.0 g, 131mmol) was dissolved in 2-propanol (400 mL).(3,4-Dihydro-2H-pyran-2-ylmethyl)-methyl-amine (50.0 g, 393 mmol,dissolved in 50 mL 2-propanol) was added and heated to reflux (˜70° C.,˜5 min.). The solution was allowed to cool down under gentle stirring(˜100 U/min.). At ˜50° C. a small portion of seeding crystals of(3,4-Dihydro-2H-pyran-2-ylmethyl)-methyl-amine (er=>99.5:0.5 by chiralHPLC, crystals derived from earlier experiments) were added. Thesolution was allowed to cool down to room temperature. During this time(18 h) a salt crystallized. The salt was filtered off and washed with asmall amount of cold 2-propanol and n-heptane to yield(3,4-Dihydro-2H-pyran-2-ylmethyl)-methyl-amine salt (36.0 g,er=83.7:16.3 by chiral HPLC). In order to receive enantiopure crystals(3,4-Dihydro-2H-pyran-2-ylmethyl)-methyl-amine salt (36.0 g,er=83.7:16.3 by chiral HPLC) was dissolved under gentle heating in2-propanol (360 mL) and crystallization was performed under the sameconditions as described above to receive(3,4-Dihydro-2H-pyran-2-ylmethyl)-methyl-amine salt (25.7 g, er=95.5:4.5by chiral HPLC). (3,4-Dihydro-2H-pyran-2-ylmethyl)-methyl-amine salt(25.7 g, er=95.5:4.5 by chiral HPLC) was dissolved in 2-propanol (350mL) and subjected to the same crystallization procedure as describedabove to yield (3,4-Dihydro-2H-pyran-2-ylmethyl)-methyl-amine salt (20.6g, 46% of the theoretical yield, er=99.5:0.5 by chiral HPLC) in clear,colourless crystals. Analytical data(3,4-Dihydro-2H-pyran-2-ylmethyl)-methyl-amine salt: Mp. 147-148° C.;[α]_(D) ²⁰=−111.1° (c=1.013, MeOH); chiral HPLC after derivatisationwith (S)-(+)-MTPA-Cl: r_(t)E1=7.17 min., r_(t)E2=8.13 min.(er_(E1/E2)=0.5/99.5), Chiralcel OD-H, n-heptane/2-propanol 98:2, flow:0.8 mL/min., UV: 240 nm; chiral GC-MS: RT-BetaDEXsm (length: 30 m,diameter: 0.25 mm), MS detector, gas: He (1.0 bar), column temperature:50-150° C. (temperature program: 5° C/min.), injection temperature: 250°C.

(3,4-Dihydro-2H-pyran-2-ylmethyl)-methyl-amine salt (9.2 g, 15.0 mmol)was dissolved in water (25 mL) and 2 N aqueous NaOH (16 mL) was added.The solution was extracted five times with dichloromethane (100 mL). Theorganic layer was washed with water (50 mL) and dried with sodiumsulphate to yield after distillation under reduced pressure(3,4-Dihydro-2H-pyran-2-ylmethyl)-methyl-amine (free base) (2.7 g, 72%,er=99.5:0.5 by chiral HPLC) as colourless liquid. Analytical data(3,4-Dihydro-2H-pyran-2-ylmethyl-methyl-amine (free base): Bp. 55-57° C.at 16 mbar. [α]_(D) ²⁰=−86.2° (c=0.725, MeOH); HPLC-MS: (M+H)³⁰=128 atr_(t)=0.619 min. (TIC), r_(t)=0.596 min. (UV), r_(t)=0.631 min. (ELS),Chromolith SpeedROD RP-18e 50-4.6 mm, solvent A: water+0.1% TFA, solventB: acetonitrile+0.1% TFA, gradient: 4% solvent Bat 0.0 min., 100%solvent B at 2.6 min., flow: 2.4 mL/min., UV: 220 nm; chiral HPLC afterderivatisation with (S)-(+)-MTPA-Cl: r_(t)E1=7.31 min., r_(t)E2=8.24min. (er_(E1/E2)=0.5/99.5), Chiralcel OD-H, n-heptane/2-propanol 98:2,flow: 0.8 mL/min., UV: 240 nm.

E) Preparation of Enantiomerically Pure1-[(R)-1-(3,4-Dihydro-2H-pyran-2-yl)methyl]-3-(2-dimethylamino-ethyl)-urea

C-(3,4-Dihydro-2H-pyran-2-yl)-methylamine (free base) (13.3 g, 118 mmol)and 1,1′-carbonyl diimidazole (28.6 g, 176 mmol) were dissolved indichloromethane (900 mL) and stirred for 2 h at room temperature. Underan Argon atmosphere N,N-Dimethyl ethylene diamine [51.2 mL, 470 mmol;dissolved in dichloromethane (250 mL)] was added and the reactionmixture stirred for 65 h at room temperature. The reaction mixture wasconcentrated to about one third volume under reduced pressure andextracted three times with water (100 mL). The organic layer was driedwith sodium sulphate and the remaining solvent removed under reducedpressure to yield1-[(R)-1-(3,4-Dihydro-2H-pyran-2-yl)methyl]-3-(2-dimethylamino-ethyl)urea(24.2 g, 91%) as pale yellow liquid. Analytical data1-[(R)-1-(3,4-Dihydro-2H-pyran-2-yl)methyl]-3-(2-dimethylamino-ethyl)-urea:HPLC-MS: (M+H)⁺=228.2 at r_(t)=1.155 min., column: Chromolith SpeedRODRP-18e 50-4, 6 mm; solvent A: water+0.1% TFA, solvent B:acetonitrile+0.1% TFA, gradient: 4% B at 0.0 min, 100% B at 2.6 min.,100% B at 3,3 min, flow: 2.4 mUmin., UV: 220 nm.

F1) Preparation of diastereomerically and enantiomerically pureexo-1-(2-Dimethylamino-ethyl)-3-(2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea

1-[(R)-1-(3,4-Dihydro-2H-pyran-2-yl)methyl)-3-(2-dimethylamino-ethyl)-urea(24.2 g, 106 mmol) and benzaldehyde (11.0 mL, 108 mmol) were dissolvedin acetonitrile (100 mL) at ˜5° C. (ice-bath). A precooled (-'5 ° C.)solution of 4-aminobenzotrifluoride (17.55 g, 109 mmol) and TFA (16.1mL) in acetonitrile (100 mL) was added and the reaction mixture stirredfor additional 2 h at ˜5° C. The reaction temperature was allowed torise to room temperature and stirred additional 90 h. The solvents wereremoved under reduced pressure, the residue dissolved in ethyl acetateand extracted three times with water (100 mL). The organic layer wasdried with sodium sulphate and the solvents removed under reducedpressure. The resulting crude diastereomeric mixture exo- andendo-1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea(48.6 g) was dissolved in dichloromethane (1.4 L) and extracted withwater (300 mL), with saturated aqueous sodium bicarbonate (300 mL), andagain with water (300 mL). The organic layer was dried with sodiumsulphate and the solvents removed under reduced pressure to receive theTHQ-urea as diastereomeric mixture exo-andendo-1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea(34.5 g). Analytical data mixture exo- andendo-1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea:HPLC-MS:endo-1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-ureawith (M+H)⁺=477 at r_(t)=1.932 min. (TIC), r_(t)=1.903 min. (UV),r_(t)=1.901 min. (ELS) andexo-1-(2-Dimethylamino-ethyl)-3-(2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-ureawith (M+H)⁺=477 at r_(t)=2.062 min. (TIC), r_(t)=2.035 min. (UV),r_(t)=2.033 min. (ELS), Chromolith SpeedROD RP-18e 50-4.6 mm, solvent A:water+0.1% TFA, solvent B: acetonitrile+0.1% TFA, gradient: 4% solventBat 0.0 min., 100% solvent B at 2.6 min., flow: 2.4 ml/min., UV: 220 nm.

The residue was subjected to column chromatography (Si60, 0.063-0.2 mm;dichloromethane/methanol 95:5 to 70:30). The suitable fractions werecollected and the solvents removed under reduced pressure to receivepure THQ diastereomerexo-1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea(19.1 g, 38%). Analytical dataexo-1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea:Mp. 121° C.; [α]_(D) ²⁰=−75.7° (c=1.02, EtOH); HPLC: r_(t)exo=10.6 min.,r_(t)endo=12.7 min., Purospher Star, solvent: ^(n)heptane/EtOH80:20+0.5% diethyl amine, flow: 1 mL/min., UV: 250 nm; HPLC-MS:(M+H)⁺=477 at r_(t)=2.062 min. (TIC), i_(t)=2.035 min. (UV), r_(t)=2.033min. (ELS), Chromolith SpeedROD RP-18e 50-4.6 mm, solvent A: water+0.1%TFA, solvent B: acetonitrile 0.1% TFA, gradient: 4% solvent B at 0.0min., 100% solvent B at 2.6 min., flow: 2.4 mL/min., UV: 220 nm.

F2) Separation of THQ Diastereomers Exo- andEndo-1-(2-Dimethylamino-ethyl)-3-(2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-ureavia preparative HPLC

The pure diastereomers of a diastereomeric mixture of urea exo- andendo-1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea(5.7 g) were separated via preparative HPLC (column: Prepbar LiChrosorbSi60 10 μm, 25×5 cm; eluent: ^(n)heptane/ethanol 85:15+0.5% diethylamine, injection: 250 mg/10 mL, flow: 80 mL/min., UV: 254 nm) to receiveTHQ-ureaexo-1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea(2.1 g, 4.4 mmol) and THQ-ureaendo-1-(2-Dimethylamino-ethyl)-3-(2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea(1.8 g, 3.8 mmol) as pure diastereomers. Analytical dataexo-1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea:see section F1 Analytical dataendo-1-(2-Dimethylamino-ethyl)-3-(2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea:HPLC-MS: (M+H)⁺=477 at r_(t)=1.932 min. (TIC), r_(t)=1.903 min. (UV),r_(t)=1.901 min. (ELS), Chromolith SpeedROD RP-18e 50-4.6 mm, solvent A:water+0.1% TFA, solvent B: acetonitrile+0.1% TFA, gradient: 4% solvent Bat 0.0 min., 100% solvent B at 2.6 min., flow: 2.4 mL/min., UV: 220 nm.

G) Preparation of Diastereomerically and Enantiomercally Pure C((2R,4aS,5R,10bS)-5-Phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-yl)-methylamine

C-[(R)-1-(3,4-Dihydro-2H-pyran-2-yl)]methylamine salt (77 g, 201 mmol)and benzaldehyde (20.7 mL, 205 mmol) were dissolved in acetonitrile (185mL) at ˜5° C. (ice-bath). A precooled (˜5 ° C.) solution of4-aminobenzotrifluoride (33.0 g, 205 mmol) and TFA (31.7 mL) inacetonitrile (185 mL) was added fast and the reaction mixture stirredfor additional 2 h at ˜5° C. The reaction temperature was allowed torise to room temperature and stirred additional 35 h. The solvents wereremoved under reduced pressure, the residue treated with water andsaturated aqueous sodium bicarbonate solution until pH 8-9 was reached.Ethyl acetate (300 mL) was added and the organic layer was extracted onetime with saturated aqueous sodium bicarbonate solution (200 mL) andthree times with water (150 mL). The organic layer was dried with sodiumsulphate and the solvents were removed under reduced pressure to yield acrude diastereomeric mixture exo- and endo-C((2R,4aS,5R,10bS)-5-Phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-yl)-methylamine(98.4 g, dr 1:1 [exo/endo]), Analytical data mixture exo- and endo-C((2R,4aS,5R,10bS)-5-Phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-yl)-methylamine:HPLC-MS: endo-C((2R,4aS,5R,10bS)-5-Phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-yl)-methylaminewith (M+H)⁺=363 at r_(t)=1.913 min. (TIC), r_(t)=1.883 min. (UV),r_(t)=1.879 min, (ELS) and endo-C((2R,4aS,5R,10bS)-5-Phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-yl)-methylaminewith (M+H)⁺=363 at r_(t)=2.021 min. (TIC), r_(t)=1.990 min. (UV),r_(t)=1.988 min. (ELS), Chromolith SpeedROD RP-18e 50-4.6 mm, solvent A:water+0.1% TFA, solvent B: acetonitrile 0.1% TFA, gradient: 4% solvent Bat 0.0 min., 100% solvent B at 2.6 min., flow: 2.4 mL/min., UV: 220 nm.

The crude diastereomeric mixture exo- and endo-C((2R,4aS,5R,10bS)-5-Phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-yl)-methylamine(80.5 g), was dissolved in 2-propanol (400 mL) under gentle heating and(2R,3R)-(−)-di-O-benzoyl tartaric acid was added. The reaction mixturewas further heated to reflux until a clear solution was formed. Thesolution was allowed to cool down to room temperature over the next 20h. For additional 4 h the reaction mixture was cooled down to 0° C.(ice-bath). During this time a salt crystallized. The salt was filteredoff and washed with a small amount of cold 2-propanol to give singlediastereomeric THQ-amine salt exo-C((2R,4aS,5R,10bS)-5-Phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-yl)-methylamine(14.7 g, 24%, er=99.9:0.1 by chiral HPLC). Analytical data exo-C((2R,4aS,5R,10bS)-5-Phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-yl)-methylamine:Mp. 169-171° C.; [α]_(D) ²⁰=−105.1° (c=1.11, MeOH); chiral HPLC:r_(t)endo=12.75 min., r_(t)exo=14.93 min. (dr_(endo/exo)=02199.8),Chirobiotic T2, methanol+0.04% ammonium trifluoro acetate (AFTA), flow:1.0 mL/min., UV: 265 nm.

H) Preparation of diastereomerically and enantiomerically pure THQ-amineexo-((2R,4aS,5R,10bS)-9-Chloro-7-fluoro-5-phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-methyl-amine

Aniline derivative (19.7 g, 135.5 mmol) and benzaldehyde (14.4 g, 135.8mmol) were dissolved in acetonitrile (250 mL) and stirred for 3 h at60-70° C. The solution was cooled down (ice-bath).(3,4-Dihydro-2H-pyran-2-ylmethyl)-methyl-amine [(2R,3R)-(−)-Di-O-benzoyltartaric acid salt] (40.0 g, 65.3 mmol) and immediately afterwards TFA(50 mL, dissolved in 100 mL acetonitrile) was added and the reactionmixture stirred for additional 1 h in an ice-bath an additional 18 h atroom temperature. The solvent and most of the TFA were removed underreduced pressure, the residue dissolved in dichloromethane (500 mL) andextracted with 2 N NaOH (350 mL). The organic layer was further dilutedwith dichloromethane (300 mL) and extracted twice with water (200 mLportions). The organic layer was extracted four times with 2 N HCl (200mL portions) and twice with water (200 mL portions). Both layers werecollected. From the aqueous layer a red-brown oil excreted overnightthat was dissolved in dichloromethane (100 mL) and the mixture wasconflated with the organic layer. The combined organic layer was driedwith sodium sulphate and the solvents were removed under reducedpressure to yield a crude diastereomeric mixture exo- andendo-((2R,4aS,5R,10bS)-9-Chloro-7-fluoro-5-phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-methyl-amine(21.05 g). Analytical data mixture exo- andendo-((2R,4aS,5R,10bS)-9-Chloro-7-fluoro-5-phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-methyl-amineHPLC-MS:endo-((2R,4aS,5R,10bS)-9-Chloro-7-fluoro-5-phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-methyl-aminewith (M+H)⁺=361 at r_(t)=1.928 min. (TIC), r_(t)=1.902 min. (UV),r_(t)=1.863 min (ELS) andexo-((2R,4aS,5R,10bS)-9-Chloro-7-fluoro-5-phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-methyl-aminewith (M+H)⁺=361 at r_(t)=2.043 min. (TIC), r_(t)=2.013 min. (UV),r_(t)=1.976 min. (ELS), Chromolith SpeedROD RP-18e 50-4.6 mm, solvent A:water+0.1% TFA, solvent B: acetonitrile+0.1% TFA, gradient: 4% solventBat 0.0 min., 100% solvent B at 2.6 min., flow: 2.4 mLimin., UV: 220 nm.The crude diastereomeric mixture exo- andendo-((2R,4aS,5R,10bS)-9-Chloro-7-fluoro-5-phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-methyl-amine(21.05 g), was dissolved in ethanol (160 mL) under gentle heating andthe reaction mixture was allowed to cool to room temperature undergentle steering over 18 hours. Finally the reaction mixture was stirredfor additional 3 h in an ice-bath. The resulting crystals were collectedby filtration and washed with a small amount of cold 2-propanole andn-heptane to yield THQ-amine salt exo--(2R,4aS,5R,10bS)-9-Chloro-7-fluoro-5-phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-methyl-amine(4.34 g, 16.7%, dr=99.5:0.5 and er>99.8:0.2 by chiral HPLC) ascolourless crystals. Analytical data exo--((2R,4aS,5R,10bS)-9-Chloro-7-fluoro-5-phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-methyl-amine:Mp. 295-296° C.; [a]_(D) ²⁰=−22.8° (c=1.9 MeOH); chiral HPLC:r_(t)E1exo=14.3 min., Chiralpak AD, n-heptane/2-propanol 95:5 +0.5%diethyl amine, flow: 0.8 mL/min., UV: 254 nm.

The remaining reaction mixture was concentrated under reduced pressure.The residue was dissolved in 2-propanol (150 mL) under gentle heating.Seeding crystals of the first crystallization were added after thereaction mixture cooled to room temperature and the reaction mixturestirred for additional 64 h. Afterwards the reaction mixture was cooledin an ice-bath for 4 h. The resulting crystals were collected byfiltration and washed with a little amount of cold 2-propanol andn-heptane respectively to give further THQ-amine saltexo-((2R,4aS,5R,10bS)-9-Chloro-7-fluoro-5-phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-methyl-amine(1.41 g, dr=90.3:9.7 and er>99.8:0.2 by chiral HPLC) as colourlesscrystals.

THQ-amine saltexo-((2R,4aS,5R,10bS)-9-Chloro-7-fluoro-5-phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-methyl-amine(0.95 g, 2.39 mmol) was dissolved in 2 N aqueous NaOH (10 mL).Dichloromethane (30 mL) was added and the reaction mixture vigorouslyshaken until all the solids were completely dissolved. The layers wereseparated and the aqueous layer was saturated with sodium chloride andextracted twice with dichloromethane (20 mL). The combined organiclayers were washed with water (5 mL) and dried with sodium sulphate toyield amine (free base)exo-((2R,4aS,5R,10bS)-9-Chloro-7-fluoro-5-phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-methyl-amine(0.84 g, 97%, dr>99.8:0.2 and er>99.8:0.2 by chiral HPLC) as colourlesscrystals. Analytical dataexo-((2R,4a8,5R,10bS)-9-Chloro-7-fluoro-5-phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-methyl-amine:Mp. 190-192° C.; [α]_(D) ²⁰=−32.9° (c=1.09, MeOH); chiral HPLC:r_(t)E1exo=15.8 min., Chiralpak AD, n-heptane/2-propanol 95:5 +0.5%diethyl amine, flow: 0.8 mL/min., UV: 254 nm.

I) Alternative preparation of diastereomerically and enantiomericallypure THQ-ureaexo-1-(2-Dimethylamino-ethyl)-34(2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea

THQ amine (−)-dibenzoyl tartaric acid saltexo-C-((2R,4aS,5R,10bS)-5-Phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-yl)-methylamine(14.5 g, 13.4 mmol) and 1,1′-carbonyl diimidazole (6.5 g, 40.1 mmol)were dissolved in dichloromethane (300 mL) and stirred for 2 h at roomtemperature. Under an Argon atmosphere N,N-Dimethyl ethylene diamine[11.7 mL, 107 mmol; dissolved in dichloromethane (70 mL)] was added andthe reaction mixture stirred for 18 h at room temperature. The solventswere removed under reduced pressure. The residue was dissolved in ethylacetate and extracted two times with 1 N aqueous NaOH (80 mL) and threetimes with water (250 mL). The organic layer was dried with sodiumsulphate and the remaining solvent removed under reduced pressure. Theresidue (approx. 15 g) was dissolved in dichloromethane (40 mL) andgentle warming. MTBE (80 mL) was added and the mixture cooled in anice-bath for 18 h. The resulting crystals were collected by filtrationand washed with an ice-cold solution of dichloromethane/MTBE 1:4 toreceive THQ amine exo-13a (6.38 g, 99%) as colourless crystals.Analytical dataexo-1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea:see section F1 analytical data.

Abbreviations: MeOH=methanol; EtOH=ethanol, PrOH=propanol,^(i)PrOH=isopropanol, DMF=dimethylformamide, THF=tetrahydrofuran,THQ=tetrahydroquinoline; DHP=3,4-Dihydro-2H-pyran, TFA=trifluoroaceticacid; CDI=1,1′-carbonyldiimidazole; MeCN (Acetonitrile),BOP=Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate, DCC=Dicyclohexylcarbodiimide,DEPBT=3-(Diethoxy-phosphoryloxy)-3H-benzo[d][1,2,3] triazin-4-one,DIC=N,N′-Diisopropylcarbodiimide,EDC=1-Ethyl-3-(3-dimethyllaminopropyl)carbodilmide hydrochloride,HATU=2-(1H-7-Azabenzotriazol-1-yl)--1,1,3,3-tetramethyl uroniumhexafluorophosphate Methanaminium,HBTU=O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate,HOAt=[1,2,3]Triazolo[4,5-b]pyridin-3-ol, HOBt=N-Hydroxybenzotriazole,HOOBt=Hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine, HCTU=1H-Benzotriazolium1-[bis(dimethylamino)methylene]-5chloro-hexafluorophosphate(1-),3-oxide, CI—HOBt=6-Chloro-1-Hydroxy-1H-Benzotriazole,PyBOP=Benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate, PyBrOP=Bromo-tris-pyrrolidino phosphoniumhexafluoro phosphate,TBTU=O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate,TDBTU=N,N,N′,N′-Tetramethyl-O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)uroniumtetrafluoroborate, TSTU=O—(N-Succinimidyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate, 4,5-Dicyanoimidazole, MTBE=tert.-Butyl methyl ether;r_(t)=retention time; UV=ultraviolet dector; TIC=total ion count (MSdetector); ELS=evaporating light scattering (detector type); Mp.=meltingpoint; Bp.=boiling point, er enantiomeric ratio; dr=diastereomericratio.

Equipment: optical rotation—Perkin Elmer Polarimeter 341 (c is measuredin g/100 mL, 100 mm cell); melting point—Büchi Melting Point B-545 (allmelting points are uncorrected); chiral HPLC—Merck-Hitachi LaChrom(consisting of D-7000 interface, L-7100 pump, L-7200 auto sampler,L-7300 column oven, L-7400 diode array detector), HPLC-MS—Agilent 1100System (MS & DAD) with ELS-detector Sedex 75 from ERC.

1. Process for the manufacture of enantiomerically enriched or purecompound of formula I:

wherein R^(a) denotes Hal, cyano, COOH, COOA, A, CF₃; R¹ denotes H, A,Aryl, Het, Hal, —(CY₂)_(n)—SA, —(CY₂)_(n)—SCF₃, —(CY₂)_(n)—SCN,—(CY₂)_(n)—CF₃, —(CY₂)_(n)—OCF₃, R, cycloalkyl, —SCH₃, —SCN, —CF₃,—OCF₃, —OA, —(CY₂)_(n)—OH, —(CY₂)_(n)—CO₂R, —(CY₂)_(n)—CN,—(CY₂)_(n)-Hal, —(CY₂)_(n)—NR₂, (CY₂)_(n)—OA, (CY₂)_(n)—OCOA, —SCF₃,(CY₂)_(n)—CONR₂, —(CY₂)_(n)—NHCOA, —(CY₂)_(n)—NHSO₂A, SF₅, Si(CH₃)₃,CO—(CY₂)_(n)—CH₃, —(CY₂)_(n)—N-Pyrolidon, (CH₂)_(n)NRCOOR, NRCOOR, NCO,(CH₂)_(n)COOR, NCOOR, (CH₂)_(n)OH, NR(CH₂)_(n)NR₂, C(OH)R₂,NR(CH₂)_(n)OR, NCOR, (CH₂)_(n)Ar, (CH₂)_(n)Het, (CH₂)_(n)R¹,(CH₂)_(n)X(CH₂)_(n)Ar, (CH₂)_(n)X(CH₂)_(n)Het, (CH₂)_(n)CONR₂,XCONR(CH₂)_(n)NR₂, N[(CH₂)_(n)XCOOR]CO(CH₂)_(n)Ar,N[(CH₂)_(n)XR]CO(CH₂)_(n)Ar, N[(CH₂)_(n)XR]CO(CH₂)_(n)XAryl,N[(CH₂)_(n)XR]SO₂(CH₂)_(n)Ar, N[(CH₂)_(n)NRCOOR]CO(CH₂)_(n)Ar,N[(CH₂)_(n)NR₂]CO(CH₂)_(n)Ar, N[(CH₂)_(n)NR₂]CO(CH₂)_(n)NRAr,N[CH₂)_(n)NR₂]SO₂(CH₂)_(n)Ar, N[(CH₂)_(n)XR]CO(CH₂)_(n)Het,N[(CH₂)_(n)XR]CO(CH₂)_(n)XHet, N[(CH₂)_(n)XR]SO₂(CH₂)_(n)Het,N[(CH₂)_(n)NRCOOR]CO(CH₂)_(n)Het, N[(CH₂)_(n)NR₂]CO(CH₂)_(n)Het,N[(CH₂)_(n)NR₂]CO(CH₂)_(n)NRHet; R², R³ denotes H, A, Hal, OA, OR; Ydenotes H, A, Hal, OR; A denotes Alkyl or Cycloalkyl, wherein one ormore H-atoms can be replaced by Hal; Hal denotes F, Cl, Br or I; Rdenotes H or A, in the case of geminal groups R together also —(CH₂)₅—,—(CH₂)₄— or —(CH₂)_(n)—X—(CH₂)_(n), or —(CH₂)_(n)—Z—(CH₂)_(n); X denotesO, S or NR¹; Q denotes CH₂—NH-A, CH₂—NH—C(O)R¹, CH₂—NH—SO₂R¹; Z denotesCH₂, X, CHCONH₂, CH(CH₂)_(n)NR¹COOR¹, CHNR¹COOR¹, NCHO, CHCON(R¹)₂,CH(CH₂)_(n)COOR¹, NCOOR¹, CH(CH₂)_(n)OH, N(CH₂)_(n)OH, CHNH₂,CH(CH₂)_(n)NR¹ ₂, CH(CH₂)_(n)NR¹ ₂, C(OH)R¹, CHNCOR¹, NCOR¹,N(CH₂)_(n)Ar, N(CH₂)_(n)Het, CHR¹, NR¹, CH(CH₂)₂Ar, CH(CH₂)_(n)Het,CH(CH₂)_(n)R¹, N(CH₂)_(n)COOR¹, CH(CH₂)_(n)X(CH₂)_(n)Ar,CH(CH₂)_(n)X(CH₂)_(n)Het, N(CH₂)_(n)CON(R¹)₂, NSO₂R¹, CHSO₂N(R¹)₂,XCONR(CH₂)_(n)N(R¹)₂, NCO(CH₂)_(n)Ar, NCO(CH₂)_(n)XAr, NSO₂(CH₂)_(n)Ar,NCO(CH₂)_(n)Ar, NCO(CH₂)_(n)NR¹Aryl, NCO(CH₂)_(n)Het, NCO(CH₂)_(n)XHet,NSO₂(CH₂)_(n)Het, NCO(CH₂)_(n)NR¹Het, N(CH₂)_(n)NR₂CH,CHO(CH₂)_(n)N(R¹)₂, CHX(CH₂)_(n)N(R¹)₂, NCO(CH₂)_(n)NR₂, R⁶ denotesunsubstituted Ar or Het which is substituted in at least one position byHal, NO₂, CN, OR, A, —(CY₂)_(n)—OR, —OCOR, —(CY₂)_(n)—CO₂R,—(CY₂)_(n)—CN, —NCOR, —COR or —(CY₂)_(n)—NR₂ or by Aryl or Het whichalso may be substituted by Hal, NO₂, CN, A, OR, OCOR, COR, NR₂, CF₃,OCF₃, OCH(CF₃)₂, R⁷ denotes (C═O)—R, (C═O)—NR₂, (C═O)—OR, H or A; Ardenotes a monocyclic or bicyclic, saturated, unsaturated or aromaticcarbocyclic ring having 6 to 14 carbon atoms which may be unsubstitutedwhich is substituted in at least one position by Hal, NO₂, CN, OR, A,—(CY₂)_(n)—OR, —OCOR, —(CY₂)_(n)—CO₂R, —(CY₂)_(n)—CN, —NCOR, —COR or—(CY₂)_(n)—NR₂ or by Hal, NO₂, CN, A, OR, OCOR, COR, NR₂, CF₃, OCF₃,OCH(CF₃)₂; Het denotes a monocyclic or bicyclic, saturated, unsaturatedor aromatic heterocyclic ring having 1 to 4 N, O and/or S atoms whichmay be unsubstituted or which is substituted in at least one position byHal, NO₂, CN, OR, A, —(CY₂)_(n)—OR, —OCOR, —(CY₂)_(n)CO₂R,—(CY₂)_(n)—CN, —NCOR, —COR or —(CY₂)_(n)—NR₂ or by Hal, NO₂, CN, A, OR,OCOR, COR, NR₂, CF₃, OCF₃, OCH(CF₃)₂; n denotes 0, 1, 2, 3, 4, 5, 6 or7; as well as their pharmaceutically acceptable derivatives, solvates,tautomers, salts and polymorphic forms comprising : reacting an anilinecompound A and an aldehyde B

with a chiral dihydropyran methylamine compound C

in the presence of a suitable solvent and a protonic acid or Lewis acidwherein R¹ to R⁶ and Q are as described above.
 2. Process according toclaim 1 wherein Q is a group —CH₂—NH(CO)R¹, —CH₂—NHSO₂R¹ or CH₂NH-A. 3.Process according to claim 1 wherein Q is CH₂NH—CH₃,CH₂NH—C(O)NH(CH₂)₂N(CH₃)₂.
 4. Process according to claim 1 wherein R⁶ isan unsubstituted Aryl.
 5. Process according to claim 1 wherein R³ isselected from H.
 6. Process according to claim 1 wherein R² is selectedfrom H.
 7. Process according to claim 1 wherein R^(a) is A.
 8. Processaccording to claim 1 wherein R^(a) is CF₃ and R⁷ is H.
 9. Processaccording to claim 1 wherein the protonic acid is TFA.
 10. Processaccording to claim 9 wherein the suitable solvent is acetonitrile. 11.Process according to claim 1 wherein Q is —CH₂—NHCH₃, R^(a) is Cl, R² isF, R³ is H, R⁷ is H and R⁶ is unsubstituted Aryl.
 12. Process for themanufacture of enantiomerically enriched or pure compounds of formula C:

wherein Q denotes CH,—NH-A, CH₂—NH—C(O)R¹, CH₂—NH—SO₂R¹ as well as theirpharmaceutically acceptable derivatives, solvates, tautomers, salts andpolymorphic forms comprising the following steps: A) treating theracemic compound C, wherein Q is CH₂NH₂ or CH₂NHA, preferably CH₂NHCH₃with a chiral acid compound in a polar solvent to give enantiomericallyenriched or pure dihydropyran methylamine salts; and optionally use abase to obtain from the dihydropyran methylamine salts the free base, orB) treating the racemic compound C, wherein Q is CH₂NH₂ or CH₂NHA,preferably CH₂NH₂ with a chiral acid compound in a polar solvent to givethe enantiomerically enriched or pure dihydropyran methylamine salts;optionally use a base to obtain from the dihydropyran methylamine saltsthe free base, and reacting the resulting compound with a group ClC(O)R¹or ClSO₂R¹ in the presence of a non nucleophilic base in a polarsolvent; or C) treating the racemic compound C, wherein is CH₂NH₂ orCH₂NHA, preferably CH₂NH₂ with a chiral acid compound in a polar solventto give the enantiomerically enriched or pure dihydropyran methylaminesalts; optionally use a base to obtain from the dihydropyran methylaminesalts the free base, and reacting the resulting compound with a primaryamine NH₂R¹ with CDI in a suitable solvent.
 13. Process according toclaim 12 for the manufacture of enantiomerically enriched or purecompounds of formula C:

wherein Q Q denotes CH₂—NH-A, CH₂—NH—C(O)R¹, CH₂—NH—SO₂R¹, as well astheir pharmaceutically acceptable derivatives, solvates, tautomers,salts and polymorphic forms comprising the following steps: treating theracemic compound C, wherein Q is CH₂NH₂ or CH₂NHA, preferably CH₂NH₂with a chiral acid compound in a polar solvent to give theenantiomerically enriched or pure dihydropyran methylamine salts;optionally use a base to obtain from the dihydropyran methylamine saltsthe free base, and reacting the resulting compound with a group ClC(O)R¹or ClSO₂R¹ in the presence of a non nucleophilic base in a polarsolvent.
 14. Process according to claim 12 for the manufacture ofenantiomerically enriched or pure compounds of formula C:

wherein Q Q denotes CH₂—NH-A, CH₂—NH—C(O)R¹, CH₂—NH—SO₂R¹ defined inclaim 1, as well as their pharmaceutically acceptable derivatives,solvates, tautomers, salts and polymorphic forms comprising thefollowing steps: treating the racemic compound C, wherein Q is CH₂NH₂ orCH₂NHA, preferably CH₂NH₂ with a chiral acid compound in a polar solventto give the enantiomerically enriched or pure dihydropyran methylaminesalts; optionally use a base to obtain from the dihydropyran methylaminesalts the free base, and reacting the resulting compound with a primaryamine NH₂R¹ with CDI in a suitable solvent.
 15. Process according toclaim 12 wherein Q is CH₂NHMe, the chiral acid is L-tosylproline, thepolar solvent ethanol and the base is NaOH: or said process wherein Q isCH₂NH₂, the chiral acid is (2R,3R)-(−)-Di-O-benzoyl tartaric acid. 16.Process according to claim 13 wherein R¹ is Methyl, the chiral salt isL-tosylproline, the polar solvent ethanol, the base is NaOH and nonnucleophilic base is TEA.
 17. Process according to claim 14 wherein R¹is CH₂—CH₂—N(CH₃)₂, the chiral salt is L-tosylproline, the polar solventethanol, the base is NaOH and the coupling agent is CDI and the solventis CH₂Cl₂.
 18. Process according to claim 1 wherein the separation ofexo and endo compounds obtained, is made by recristallization withchiral salts or acid.
 19. Process according to claims 1, whereincompound C is obtained by A) treating the racemic compound C, wherein Qis CH₂NH₂ or CH₂NHA, preferably CH₂NHCH₂ with a chiral acid compound ina polar solvent to give enantiomerically enriched or pure dihydropyranmethylamine salts; and optionally use a base to obtain from thedihydropyran methylamine salts the free base; or B) treating the racemiccompound C, wherein Q is CH₂NH₂ or CH₂NHA, preferably CH₂NH₂ with achiral acid compound in a polar solvent to give the enantiomericallyenriched or pure dihydropyran methylamine salts; optionally use a baseto obtain from the dihydropyran methylamine salts the free base, andreacting the resulting compound with a group ClC(O)R¹ or ClSO₂R¹ in thepresence of a non nucleophilic base in a polar solvent; or C) treatingthe racemic compound C, wherein Q is CH₂NH₂ or CH₂NHA, preferably CH₂NH₂with a chiral acid compound in a polar solvent to give theenantiomerically enriched or pure dihydropyran methylamine salts;optionally use a base to obtain from the dihydropyran methylamine saltsthe free base, and reacting the resulting compound with a primary amineNH₂R¹ with CDI in a suitable solvent.
 20. Process for the manufacture ofenantiomerically enriched or pure compounds of formula Ia or Ib

as well as their pharmaceutically acceptable derivatives, solvates,tautomers, salts and polymorphic forms, for formula Ia byrecristallization with (2R,3R)-(−)-Di-O-benzoyl tartaric acid salt inEtOH, or for formula Ib by recristallization with HCl in EtOH. 21.Process according to claim 20 for the manufacture of enantiomericallyenriched or pure compounds of formula Ia by recristallization with(2R,3R)-(−)-Di-O-benzoyl tartaric acid salt in EtOH.
 22. Processaccording to claim 20 for the manufacture of enantiomerically enrichedor pure compounds of formula Ib by recristallization with HCl in EtOH.23. Process according to claim 12 for the manufacture ofenantiomerically enriched or pure compounds of formula C:

wherein Q denotes CH₂—NH-A, CH₂—NH—C(O)R¹, CH₂—NH—SO₂R¹, as well astheir pharmaceutically acceptable derivatives, solvates, tautomers,salts and polymorphic forms comprising the following steps: treating theracemic compound C, wherein Q is CH₂NH₂ or CH₂NHA, preferably CH₂NHCH₃with a chiral acid compound in a polar solvent to give enantiomericallyenriched or pure dihydropyran methylamine salts; and optionally use abase to obtain from the dihydropyran methylamine salts the free base.